Inhaled Nitric Oxide and Cerebral Malaria: Basis of a Strategy for Buying Time for Pharmacotherapy

1Brigham and Women's Hospital, Harvard Medical School 2Institut de recherche pour le développement, France 3Epicentre Research Base, Mbarara, Uganda 4Mbarara University, Mbarara, Uganda 5Massachusetts General Hospital, Harvard Medical School.
The Pediatric Infectious Disease Journal (Impact Factor: 2.72). 07/2012; 31(12). DOI: 10.1097/INF.0b013e318266c113
Source: PubMed


There are approximately 225-600 million new malaria infections worldwide annually, with severe and cerebral malaria representing major causes of death internationally. The role of nitric oxide (NO) in the host response in cerebral malaria continues to be elucidated, with numerous known functions relating to the cytokine, endovascular, and cellular responses to infection with Plasmodium falciparum. Evidence from diverse modes of inquiry suggests NO to be critical in modulating the immune response and promoting survival in patients with cerebral malaria. This line of investigation has culminated in the approval of two phase II randomized prospective clinical trials in Uganda studying the use of inhaled NO as adjuvant therapy in children with severe malaria. The strategy underlying both trials is to use the sytemic anti-inflammatory properties of inhaled NO to "buy time" for chemical anti-parasite therapy to lower the parasite load. This paper reviews the nexus of malaria and nitric oxide biology with a primary focus on cerebral malaria in humans.

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    • "In fact, it has been widely demonstrated that murine experimental cerebral malaria (ECM)-induced endothelial dysfunction depends on the adhesion of parasitized erythrocytes to cerebral microvasculature [4] [5] [6]; the production of inflammatory mediators, such as TNF-α, as well as increased expression of adhesion molecules on endothelial cells [7,8]. Recent advances concerning malaria treatment have suggested that an adjuvant therapy targeting endothelial activation improves patient outcome [9] [10] [11]. Indeed, prevention of BBB disruption has been shown to diminish ECM [3], which can be achieved via pharmacological induction of the stress-responsive protein heme oxigenase-1 (HO-1) and exposure to carbon monoxide, the end-product of HO-1 activity [12]. "
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    • "Decreased Ang-1 or increased Ang-2 levels in serum, as measured by an increasing Ang-2/Ang-1 ratio, is associated with CM and can predict disease severity in adults and children (Conroy et al., 2009, 2010; Lovegrove et al., 2009; Jain et al., 2011; Prapansilp et al., 2013). Ang-1 and Ang-2 are regulated by nitric oxide, a signaling molecule in many processes, which is produced in the endothelium from L-arginine and causes vasorelaxation, vascular quiescence, down-regulation of endothelial adhesion molecules and reduces thrombosis (Bergmark et al., 2012). Nitric oxide bioavailability is reduced in SM and relates to fatal outcome and several groups have suggested that this could be linked to low L-arginine levels during malaria infection (Anstey et al., 1996; Lopansri et al., 2003; Yeo et al., 2007, 2008). "
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